Process for preparing 4-substituted azetidinones

ABSTRACT

A process for preparing 3-4-cis-β,β-(4)-substituted and 3-4-trans,β,α-(4)-substituted azetidinones is provided. Also provided are novel 4,4-disubstituted azetidinones.

This application is a division of application Ser. No. 07/410,173, filedSept. 20, 1989, now U.S. Pat. No. 4,992,545.

BACKGROUND OF THE INVENTION

This invention relates to β-lactam antibiotics. In particular, itrelates to a process for preparing certain 4-substituted azetidinones,primarily useful as intermediates to β-lactam antibiotics.

Among the newer β-lactam antibiotics currently under investigation arethe 1-carba(1-dethia)-3-cephem-4-carboxylic acids. These β-lactamcompounds provide significant synthetic challenges. One of the morenoteworthy approaches to total synthesis of1-carba(1-dethia)-3-cephem-4-carboxylic acids is the asymmetric routedescribed by Evans, et al., U.S. Pat. No. 4,665,171.

One further route to cis-chiral azetidinones with readily derivatized4-allyl (and substituted allyl) groups, is provided by Blaszczak, U.S.Pat. No. 4,771,134. The Blaszczak method utilizes a 4-acetoxyazetidinone as starting material to provide 4-(substitutedselenyl)azetidinones. The 4-(substituted selenyl)azetidinones areconverted to 4-allyl(and substituted allyl)azetidinones under freeradical conditions using a (2-substituted or unsubstituted) allyl tinreagent.

SUMMARY OF THE INVENTION

A process for preparing cis,β,β(and trans β,α)-3-protected amino-4-alkylazetidinones is provided via alkylation of trans,β,α-3-protectedamino-4-phenylsulfonyl azetidinones followed by reductive elimination ofthe phenylsulfonyl moiety.

As an example of the present invention,3-β-phenoxyacetylamino-1-t-butyldimethylsilyl-4-α-phenylsulfonyl-azetidin-2-oneis treated with n-butyllithium and 1-bromo-4-butene to provide3-β-phenoxyacetylamino-1-t-butyldimethylsilyl-3-α-phenylsulfonyl-3-β-1-butene-4-yl-azetidin-2-one.The 4-disubstituted intermediate can then be readily converted to thecorresponding 4-butenyl derivative by treatment with a hydride reducingagent, such as lithium tri-tert-butoxyaluminohydride, or by electrolyticreduction, or by dissolving metal reduction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing compounds ofFormula (I): ##STR1## wherein R is a protected amino group; hydroxy(C₁-C₄)alkyl, protected hydroxy(C₁ -C₄)alkyl hydrogen; C₂ -C₄ alkenyl; C₁-C₄ alkyl or hydrogen; R² is C₁ -C₁₂ alkyl, C₁ -C₁₂ substituted alkyl,C₂ -C₆ alkenyl, C₂ -C₆ substituted alkenyl, C₂ -C₆ alkynyl, C₂ -C₆substituted alkynyl; and R³ is an amide-protecting group, C₁ -C₆ alkyl,C₁ -C₆ substituted alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, or hydrogen;which comprises:

(a) reaction of a compound of Formula (II): ##STR2## wherein R¹ istriphenylphosphonium, --SO₂ R', CN, --SiR'₃ ', ##STR3## or --CO₂ R'wherein R' is C₁ -C₆ alkyl, phenyl, substituted phenyl, phenyl C₁ -C₆alkyl, or C₁ -C₆ substituted alkyl, with strong base in the presence ofa compound of the formula R² -L, wherein L is a leaving group; followedby

(b) reduction with a hydride reducing agent, reduction under dissolvingmetal conditions or reduction under electrolytic reduction conditions.

As further aspects of the present invention, there are provided theindividual processes (a) and (b), above.

In the above formulae, the undulating lines emanating from the 3- and4-positions of the β-lactam ring denote the α and β configurations, aswell as compounds wherein there is a mixture of α- and β-isomers.

In the above formulae, the term "C.sub. -C₁₂ alkyl" denotes suchradicals as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, amyl, tert-amyl, hexyl, dodecyl, lauryl and the like. Thepreferred "C₁ -C₁₂ alkyl" groups are methyl, and t-butyl.

The term "C₁ -C₁₂ substituted alkyl" denotes the above C₁ -C₁₂ alkylgroups that are substituted by one or two halogen, hydroxy, protectedhydroxy, amino, protected amino, C₁ -C₇ acyloxy, nitro, carboxy,protected carboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylaminoor C₁ -C₄ alkoxy groups. The substituted alkyl groups may be substitutedonce or twice with the same or with different substituents.

Examples of the above substituted alkyl groups include the cyanomethyl,nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl,aminomethyl, carboxymethyl, allyloxycarbonylmethyl,allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl,methoxyethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl,2-amino(iso-propyl), 2-carbamoyloxyethyl, and the like. A preferredgroup of examples within the above "C₁ -C₁₂ substituted alkyl" groupincludes the substituted methyl group, in other words, a methyl groupsubstituted by the same substituents as the "C₁ -C₁₂ substituted alkyl"group. One of ordinary skill will appreciate that there exist groupswithin the above definition as well as other groups defining R² whichcould be incompatible for use with a strong base and, of course, suchgroups are excluded from the definition herein.

The term "C₂ -C₆ alkenyl" denotes groups possessing between two and sixcarbon atoms and at least one double carbon-carbon bond. A few examplesof such groups are vinyl, 1-propene-2-yl, 1-butene-4-yl, 1-pentene-5-yl,1-hexene-6-yl, 1-propene-1-yl, 1-butene-1-yl, 1-pentene-1-yl,1-hexene-1-yl, and like groups.

The term "C₂ -C₆ substituted alkenyl" denotes the above C₂ -C₆ alkenylgroups that are substituted by one or more halogen, hydroxy, protectedhydroxy, protected amino, C₁ -C₇ acyloxy, nitro, carboxy, protectedcarboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino or C₁ -C₄alkoxy groups. The C₂ -C₆ substituted alkenyl groups may be substitutedonce or twice with the same or with different substituents.

The term "C₂ -C₆ alkynyl" denotes groups possessing between two and sixcarbon atoms and at least one triple carbon-carbon bond. A few examplesof such groups include ethynyl, 1-propyne-2-yl, 1-butyne-4-yl,1-pentyne-5-yl, 1-butyne-1-yl, and like groups.

The term "C₂ -C₆ substituted alkynyl" denotes the above C₂ -C₆ alkynylgroups that are substituted by one or more halogen, hydroxy, protectedhydroxy, protected amino, C.sub. -C₇ acyloxy, nitro, carboxy, protectedcarboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino, or C.sub.-C₄ alkoxy groups. The C₂ -C₆ substituted alkynyl groups may besubstituted once or twice with the same or different substituents.

The term "substituted phenyl" denotes a phenyl ring substituted with oneor more halogen, hydroxy, protected hydroxy, protected amino, C₁ -C₇acyloxy, nitro, cyano, methylsulfonylamino, or C.sub. -C₄ alkoxy groups.The phenyl ring may be substituted one or more times with the same ordifferent substituents.

In the above process, the term "protected amino group" refers to anamino group substituted by groups commonly employed to block or protectthe amino functionality while reacting other functional groups on thecompound. Examples of such amino-protecting groups include the formylgroup, the trityl group, the phthalimido group, the trichloroacetylgroup, the chloroacetyl, bromoacetyl, iodoacetyl, phenoxyacetyl andphenylacetyl groups, urethane-type blocking groups such asbenzyloxycarbonyl, allyloxycarbonyl 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxycarbonyl, 2-(4-xenyl)iso-propoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-xyloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentyloxycarbonyl, 1-methylcyclopentyloxycarbonyl,cyclohexyloxycarbonyl, 1-methylcyclohexyloxycarbonyl,2-methylcyclohexyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino) ethoxycarbonyl,9-fluorenylmethoxycarbonyl ("FMOC"), 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,isobornyloxycarbonyl, 1-piperidyloxycarbonyl, and the like; thebenzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, thediphenylphosphine oxide group, and like amino-protecting groups. Thespecies of amino-protecting group employed is not critical so long asthe derivatized amino group is stable to the condition of subsequentreaction(s) on other positions of the molecule and can be removed at theappropriate point without disrupting the remainder of the molecule.Preferred amino-protecting groups are the t-butoxycarbonyl, andphenoxyacetyl groups. Similar amino-protecting groups used in thecephalosporin, penicillin and peptide art are also embraced by the aboveterms. Further examples of groups referred to by the above terms aredescribed by J. W. Barton, "Protective Groups in Organic Chemistry", J.G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley andSons, New York, N.Y., 1981, Chapter 7.

In the above process, the term "amide-protecting group" refers to groupstypically used to protect the amide nitrogen of a β-lactam moiety. Suchprotecting groups include tri(C₁ -C₆ alkyl)silyl groups, such astrimethylsilyl, triethylsily, t-butyldimethylsilyl (TBDMS), trityl,allyl, or benzyl. Also encompassed by the term "amide-protecting group"are groups which serve to protect the β-lactam nitrogen from unwantedside reactions but which are normally not thought of as mere protectinggroups, but rather are groups which possess useful functionality forfurther synthesis. Such groups include the C₁ -C₆ substituted alkylgroup and the the C₁ -C₆ alkyl group.

As used herein, the term "protected carboxy group" refers to one of theester derivatives of the carboxylic acid group commonly employed toblock or protect the carboxylic acid group while reactions are carriedout on other functional groups on the compound. Examples of suchcarboxylic acid-protecting groups include allyl, 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl,2,2'4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl,4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4''-trimethoxytrityl,2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl,2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl,allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and likemoieties. The species of carboxy-protecting group employed is notcritical so long as the derivatized carboxylic acid is stable to thecondition of subsequent reaction(s) on other positions of the moleculeand can be removed at the appropriate point without disrupting theremainder of the molecule. In particular, it is important not to subjectthe carboxy-protected molecule to strong nucleophilic bases. Furtherexamples of these groups are found in E. Haslam, "Protective Groups inOrganic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,1973, Chapter 5, and T. W. Greene, "Protective Groups in OrganicSynthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 5.

The term "protected hydroxy group" refers to a hydroxy group protectedwith a conventional protecting group. (See, for example, ProtectiveGroups in Organic Synthesis by Theodora W. Greene, New York, John Wiley& Sons, 1981, Ch. 2.)

The term "strong base" includes such reagents as n-butyl lithium,t-butyllithium, sec-butyllithium, lithium diisopropyl amine, lithiumhexamethyldisilazane, and the like. The only functional limitation onsaid reagent is that it not react in a destructive manner with otherfunctionality in the molecule.

In the above process, the term "leaving group" (L) has conventionalmeaning; i.e., L can be chloro, bromo, iodo, mesyl, tosyl, imidazolo,trifluoromethanesulfonyl, and the like.

The term "hydride reducing agent", as used herein, refers to compoundssuch as NaBH₄, NaCNBH₃, ##STR4## Zn(BH₄)₂, LiAlH[O--C(CH₃)₃ ]₃, n-Bu₄NBH₄ KB[CH(CH₃)C₂ H₅ ]₃ H(K-Selectride®), LiCNBH₃,LiAlH₄ [(CH₃ OCH₂ CH₂O)₂ AlH₂ ]Na, LiB(CH₃ CH₂)₃ H, (CH₃)₄ NBH₄, diborane, Na(CH₃ O)₃ BH,lithium trisiamylborohydride, diisobutylaluminium hydride, potassiumtrisiamylborohydride, Ca(BH₄)₂, NaBH₄ --CeCl₃, and the like.

The choice of hydride reducing agent in the above process step (b) iscrucial in determining stereoselectivity of the eventual orientation ofthe group represented by R². For example, utilization of LiAlH[OC(CH₃)₃]₃ provides predominantly cis (β, β) isomer while tetra-n-butyl ammoniumborohydride provides predominantly (β, α) (3 and 4 positions,respectively) trans-isomer. Further, reduction of substrates of formulaII above wherein R² and R are trans (β, α or) under appropriateconditions, for example lithium aluminum tri-t-butoxy hydride, resultsin essentially all cis (β, β) product. Thus, as a preferred aspect ofthe present invention, the second step (B) of the above process proceedsin an essentially stereoselective manner to provide compounds of theformula ##STR5##

Further, in another preferred aspect of the present invention, thesecond step (B) of the above process proceeds to provide compounds whereR² is α, by using, for example, tetra-n-butylammonium borohydride.

Thus, tetra-n-butylammonium borohydride and LiAlH[OC(CH₃)₃ ]₃ are mosthighly preferred as hydride reducing agents.

As a further aspect of the present invention, there are providedintermediates of Formula (III) ##STR6## wherein R, R₁, R₂, and R₃ are asdefined above, which are formed as a result of step (A) of the processas described above.

In the process of the present invention, the starting materials offormula (II) may be obtained using chemical methodology known in theβ-lactam art. See, for example, preparation 2, below. In like manner,compounds of formula II where R¹ is other than phenylsulfonyl may besynthesized using known methodology.

The first step in the process involves alkylation of a compound offormula (II). This reaction is preferably run at reduced temperature inpolar aprotic solvents such as tetrahydrofuran, diethyl ether,dimethoxyethane, and the like. A strong base such as n-butyllithium ispreferred, although other bases as described herein will also beefficacious. If the orientation of the R group is β and the R¹ group isα, the alkylation will result in a product wherein R¹ is essentially inthe β orientation, although small amounts of β, α (R, R¹) can beisolated.

Irrespective of the orientation of the alkylation product (formula III),reduction will provide either cis (ββ) or trans (β, α) material, whichcan then be used as an intermediate for the synthesis of a wide varietyof desirable β-lactam antibiotics such as the monobactams, carbapenems,and 1-carba(1-dethia)cephalosporins. One reduction method utilizes ahydride reducing agent as described above. Accordingly, as a preferredaspect of the present invention, there is provided the utilization ofLiAlH(--O--C(CH₃)₃)₃ to afford compounds of formula 1 wherein R and R²are both cis, β,β. In this regard, the various R² groups can then bederivatized into other useful β-lactam intermediates.

For example, if R² is 4-butene-1-yl, (A) ##STR7## oxidation with KMnO₄will provide cis-4-oxo-3-[(protected) amino]-2-azetidine propanoic acid(B) ##STR8## which can be used in the synthesis of penems and1-carba(1-dethia) cephalosporins. (See for example, C. C. Bodurow, etal., Tetrahedron Letters, Vol. 30, No. 18, pp. 2321-2324, 1989).

Another method of reduction (removal) of the R¹ group is theconventional dissolving metal reduction, for example Na amalgam/ethanol.See, for example, J. Chem. Soc., 4881, 1952; Tetrahedron Letters, p.835, 1973; or Journal of Organic Chemistry, 38, 2447 (1973).

Finally, the R¹ group in formula (2) may be removed by electrolyticmeans. For example the method of Justice, et al., as taught in U.S. Pat.No. 4,588,484, incorporated herein by reference, may be utilized toreduce (remove) the R¹ group after alkylation (insertion of R²).

The following Examples are set forth to further illustrate the inventionbut are in no manner to be construed as limiting the scope thereof. Thefollowing abbreviations are used herein: NMR=nuclear magnetic resonancespectrum; IR=infrared spectrum; UV=ultraviolet spectrum; MS=massspectrum; OR=optical rotation.

Experimental Section Preparation 1 4-(S)-Acetoxyazetdinones

The title compounds may be synthesized from penicillin via themethodology taught in Blaszczak, U.S. Pat. No. 4,771,135, especiallycolumns 15-18, incorporated herein by reference.

Preparation 2 3-β-Phenoxyacetylamino-4-α-phenylsulfonylazetidin-2-one

A 27.0 g (100 mM) sample of3-β-phenoxyacetylamino-4-α-acetoxy-azetidin-2-one was dissolved in 250ml of dimethylformamide along with 16.4 g (100 mM) of sodiumphenylsulfinate and stirred at room temperature for 24 h. The reactionmixture was then diluted with H₂ O and extracted with ethyl acetate(3×500 mL). The combined ethyl acetate portions were then washedsequentially with 1N HCl (1×), H₂ O (5×) and brine (1×), dried overanhydrous MgSO₄, filtered and partially concentrated. The mother liquorswere then diluted with hexane and the resulting solid filtered and driedin vacuo. Yield=29.1 g (81%) of a yellow powder.

¹ H NMR: (300 MHZ, (CH₃)₂ SO-d₆) δ9.38 (S, 1H), 8.98 (d, J=7Hz, 1H),7.95-6.90 (M, 10H), 5.02 (d, J=1Hz,1H), 4.99 (dd, J=7, 1Hz, 1H) and 4.57(ABq, 2H).

IR: (KBr) 3299, 3294, 1807, 1781, 1696, 1532, 1491, 1445, 1312, 1303,1249, 1230, 1149, 1085, and 1066 cm-¹.

UV: (ethanol) λ max 322(ε=209), 267 (ε=2160), and 217 (ε=17,100)

MS: m/e 360 (M+)

OR: [α]_(D) =-29.9° (C=0.5 in DMSO)

Anal: (C₁₇ H₁₆ N₂ O₅ S) C,H,N.

Preparation 31-t-Butyldimethylsilyl-3-β-phenoxyacetylamino-4-α-phenylsulfonylazetidin-2-one

A 28.5 g (79.16 mM) sample of3-β-phenoxyacetylamino-3-α-phenylsulfonylazetidin-2-one and 25 ml ofdiisopropylethylamine were dissolved in 250 ml of tetrahydrofuran andtreated with 13.13 g (87.08 mM) of t-butyldimethylsilyl chloride andallowed to stir at room temperature for 24 h. The solvent was removed invacuo and the residue was triturated with hexane, dissolved in ethylacetate, washed sequentially with 1NHCl, H₂ O, and brine. The ethylacetate solution was then dried over anhydrous Na₂ SO₄, filtered andconcentrated to afford a yellow foam.

The resulting foam was triturated with hexane and purified by liquidchromatography over normal phase silica gel (CH₂ Cl₂ /ethyl acetate) toafford 29.0 g (77%) of the title compound as a yellow-white solid.

¹ H NMR: (300 MHz, CDCl₃) δ 8.0-6.7 (M, 11H), 5.02 (d, J=1Hz, 1H), 4.78(dd, J=7, 1Hz, 1H), 4.38 (ABq, 2H), 1.06 (S, 9H), 0.4 (S,3H), and 0.3(S,3H).

IR: (CHCl₃) 1776, 1695, 1599, 1524, 1495, 1471, 1448, 1441, 1323, 1310,1287, 1256, 1235, 1228, 1217, 1214, 1211, 1209, 1175, 1156, 1082, 1062,896, 827, 814 and 807

UV: (ethanol) λ max 266 (ε=2060) and 217 (ε=18,100).

MS:m/e 417 (m-C₄ H₉)

OR: [α]_(D) =+5.5° (C=0.5 in methanol)

Anal: (C₂₃ H₃₀ N₂ O₅ SSi) C, H, N

Example 1 3-β-Phenoxyacetylamino-4-β-1-butene-4-yl-azetidin-2-one A.Alkylation

A 0.995 g (2.096 mM) sample of1-t-butyldimethylsilyl-3-β-phenoxyacetylamino-4-α-phenylsulfonylazetidin-2-onewas dissolved in 10 ml of tetrahydrofuran and cooled to -78° C. A 3.36ml (1.56M in hexane, 5.24 mM) sample of n-butyllithium was then addedand the solution stirred for 30 min. and then treated with 0.425 ml(4.192 mM) of 4-bromo-1-butene. The reaction mixture was allowed to stirat -78° C for 5 min., and then at -28° C. for 5 h. The reaction mixturewas then quenched with pH 4 buffer, extracted with ethyl acetate (3×).The combined ethyl acetate portions were dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. Trituration of the resulting solidwith diethyl ether provided 393.4 mg. The mother liquors werecrystallized in diethyl ether to provide 119.5 mg (combined yield =47%)of 1-t-butyldimethylsilyl-3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-(1-butene-4-yl)-azetidin-2-one.

¹ H NMR: (300 MHZ, CDCl₃) ε8.05 (d, J=8Hz, 1H), 7.8-6.6 (m,10H), 6.15(d, J=8Hz, 1H), 5.42 (m, 1H), 4.98 (dd, J=6, 1 Hz, 1H), 4.92 (dd, J=12,1 Hz 1H), 4.4 (ABq, 2H), 2.3 (m, 1H), 2.15 (M, 1H), 1.85 (M, 1H), 3.35(M, 1H), 1.1 (S,9H), 1.45 (S,3H), 1.40 (S,3H).

IR: (CHCl₃): 2960, 2932, 1766, 1701, 1599, 1517, 1494, 1472, 1447, 1441,1321, 1311, 1291, 1264, 1257, 12 1216, 1206, 1204, 1174, 1152, 1083,845, 834, 823, and 810 cm-¹.

UV: (ethanol) λ max 274 (ε=1890), 267 (ε=2260), and 218 (ε=18,000).

MS: m/e 471 (M-C₄ H₉)

OR: [α]_(D) =+16.0° (C=0.5 in methanol)

Anal: (C₂₇ H₃₆ N₂ O₅ SSi) C, H, N

B. Deprotection

A 2.00 g (3.795 mM) portion of the product of Part B above, wasdissolved in 100 ml of (1:1) tetrahydrofuran/1N HCl and stirred at 0° C.for 30 min., then at room temperature for 5 h. The solvent was removedin vacuo (azeotroped with toluene and benzene) to afford 1.69 g of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-(1-butene-4)-yl-azetidin-2-one.

¹ H NMR: (300 MHz, (CH₃)₂ SO-d₆) δ 9.75 (S, 1H), 9.18 (d, J=8Hz, 1H),8.0-6.8 (M, 10H), 5.7 (m, 1H), 5.4 (d, J=8Hz, 1H), 4.9 (M, 2H), 4.6(ABq, 2H), 2.2 (M, 2H), 1.9 (M, 1H), and 1.65 (M, 1H).

IR: (CHCl₃): 1792, 1700, 1516, 1495, 1234, 1230, 1226, 1205, and 1153cm⁻¹.

UV: (ethanol) λ max 275 (ε=2440), 268 (ε=2760), and 216 (ε=16,800)

MS: m/e 415 (M+)

OR: [α]_(D) =-1.4 (C=0.5 in methanol)

Anal: Calc. or C₂₁ H₂₂ N₂ O₅ S: C, 60,86; H, 5.35; N, 6.76. FoundC,59.47; H,5.66; N, 7.60.

C. Reduction

A 1.00 g (2.245 mM) sample of the crude product from Part B above, wasdissolved in 15 ml of tetrahydrofuran and cooled to 0° C. To thissolution was added 1.23 g of lithium tri-tert-butoxyaluminohydride. Thereaction mixture was stirred at 0° C. for about 30 min., and thenquenched with saturated aqueous NaHCO₃ solution and diluted with ethylacetate and 1NNaOH. The aqueous layer was extracted (3×) with CH₂ Cl₂/isopropanol and the combined organic layers were, in turn, washed withbrine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo.The resulting residue was triturated with hexane (1×) and then withdiethyl ether (3×), thereby removing transsubstituted contaminant. Theresulting solid was dried in vacuo to provide 480.0 mg (78% yield) of3-β-phenoxyacetyl-4-β- (1-butene-4-yl)-azetidin-2-one.

¹ H NMR: (300 MHZ, (CH₃)₂ SO-d₆) δ 8.9 (d, J=8Hz,

1H), 8.4 (S, 1H), 7.3 (M, 2H), 6.95 (M, 3H), 6.75 (M, 1H), 5.10 (dd,J=8, 4Hz, 1H), 5.02-4.90 (M, 2H), 4.56 (S, 2H), 3.64 (M, 1H), 2.0 (M,2H), and 1.5 (M, 2H).

IR: (CHCl₃): 1770, 1689, 1495, 1236, 1224, 1220, 1217, 1213, and 1210cm-¹.

UV: (ethanol) λ max 275 (ε=1200) and 269 (ε=1430).

MS: m/e 274 (M+)

OR: [α]_(D) =61.9° (C=0.5 in methanol)

Anal: (C₁₅ H₁₈ N₂ O₃) C, H, N.

Preparation 4 3-β-Phenoxyacetylamino-4-β-[2-carboxyethyl]azetidin-2-one

A 31.9 mg (0.116 mM) of the product of Example 1 was combined with 8 mlof (1:1) acetone/H₂ O, 0.2 ml of acetic acid, and 73.5 mg (0.466 mM) ofKMnO₄ and stirred at 0° C. for 6 h. The reaction mixture was thenquenched with sodium sulfite/1NHCl/ethyl acetate. The ethyl acetatelayer was dried over anhydrous MgSO₄, filtered, and concentrated invacuo to afford a white solid. The resulting solid was triturated withethyl ether and dried in vacuo to afford 23.4 mg (70% yield) of thetitle compound.

¹ H NMR: (300 MHz, (CH₃)₂ SO-d⁶) 12.15 (brS, 1H), 8.92 (d, J=8H, 1H),8.38 (S, 1H), 7.3 (M,2H), 6.92 (M, 3H), 5.08 (dd, J=8, 4Hz 1H), 4.57(ABq, 2H), 3.64 (m, 1H), 2.2 (M, 2H), and 1.65 (M, 2H) IR: (KBr): 3321,3091, 3085, 3077, 1744, 1736, 1715, 1665, 1533, 1489, 1405, 1235, 1194,1181, and 1174 cm⁻¹.

UV: (methanol) λ max 275 (ε=1040), 268 (ε=1280, and 217 (ε=758)

MS: m/e 274 (M+-OH) Anal: (C₁₄ H₁₆ N₂ O₅) C, H, N.

Example 23-β-Phenoxyacetylamino-4-α-phenylsulfonyl-4-β-(3-phenyl-2-propene-1-yl)-1-t-butyldimethylsilyl-azetidin-2-oneA. Alkylation

A 1.00g (2.11 mm) sample of1-t-butyldimethylsilyl-3-β-phenoxyacetylamino-4-α-phenylsulfonyl-azetidin-2-onewas dissolved in 10 ml of THF, cooled to -78° C., and treated with 4.7ml (6.33 mm; 1.11M in hexane) of n-butyllithium and stirred for about 10min. The reaction mixture was then treated with 415.8 mg (2.11 mm) ofcinnamyl bromide and stirring was continued at -28° C. for 2h, followedby the addition of 200 mg of cinnamyl bromide. The reaction mixture wasthen quenched with pH4 buffer and extracted with CH₂ Cl₂. The CH₂ Cl₂portion was washed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to afford 1.3075 g of 1-t-butyldimethylsilyl3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-(3-phenyl-2-propene-2-oneas a yellow oil, used in the next step without purification.

B. Deprotection

The product from part A above was dissolved in a mixture composed of 10ml of 1N HCl and 10 ml of THF and stirred at room temperature for 20 h.The reaction mixture was then diluted with ethyl acetate and brine,salted, and extracted (3×) with ethyl acetate. The combined ethylacetate portion was dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to afford 1.26 of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-(3-phenyl-2-propene-1-yl)-azetidin-2-oneas a yellow solid, used in the next step without purification.

C. Reduction

A 1.26g sample of the material from part B, above, was dissolved in 30ml of THF and cooled to 0° C. The substrate was then treated with 1.61g(6.33 mm) of lithium tri-tert-butoxy aluminum hydride in portions andstirred at 0° C. for 4 h, then at room temperature for 16 h. Thereaction mixture was then quenched with acetone, then ethyl acetate,then aqueous NaOH. The reaction mixture was then extracted with ethylacetate (4×) and the combined ethyl acetate portions were washed withbrine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuoto afford 890 mg of a yellow solid.

This crude product was boiled in 25 ml of diethyl ether and then cooled.The resulting preciptate was triturated with diethyl ether to afford 330mg of a yellow white solid.

¹ H NMR (300 MHz, DMSO-d₆): δ 9.0 (d, 1H, J=8 Hz), 8.45 (s, 1H), 7.4-6.8(m, 10 H), 6.6-6.2 (m, 2H), 5.2 (dd, 1H, J=5, 8 Hz), 4.8 (S, 2H), 3.8(m, 1H) and 2.35 (m, 2H)

IR (CHCl₃): 3420, 3020, 1771, 1686, 1523, 1495, 1237, and 1214 cm⁻¹.

MS: m/e 336 (m⁺)

UV (ethanol) λmax =304 (ε=8940), 276 (ε=6650), and 254 (ε=13,700)

OR: [α]_(D) =⁺ 16.9 (C=0.59 in CH₃ OH)

Elemen. Anal (C₁₉ H₂₀ N₂ O₃):

    ______________________________________                                        Theory (%)     Found (%)                                                      ______________________________________                                        C          71.41   C            69.15                                         H           5.99   H             5.31                                         N           8.33   N             7.84                                         ______________________________________                                    

Example 3 3-β-Phenoxyacetylamino-4-β-dodecyl-azetidin-2-one A.Alkylation

A 1.00g (2.11 mm) sample of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-1-t-butyldimethylsilylazetidin-2-onewas dissolved in 10 ml of THF and treated with n-butyllithium (3.38 ml;5.275 mm; 1.56M in hexane) and dodecylbromide (1.01 ml; 1.052g; 4.22 mm)in the general procedure of Examples 1,2 and 3, to provide, after columnchromatography over silica gel (hexane/ethyl acetate) 886.8 mg of3-β-phenoxyacetylamino- 4-α-phenylsulfonyl-4-β-dodecyl-1-t-butyldimethylsilyl-azetidin-2-one as a yellowfoam. (65% yield)

¹ H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, 1H, J=8 Hz), 7.8-6.6 (m, 10 H),6.16 (d, 1H, J=8 Hz), 4.4 (ABq, 2H), 1.4-1.0 (m 22 H), 1.1 (S, 9H), 0.9(t, 3H, J=7 Hz), 0.43 (S, 3H), and 0.39 (S, 3H).

IR (CHCl₃): 3024, 2955, 2930, 1766, 1702, 1600, 1518, and 1495 cm⁻¹.

MS: m/e =643 (M⁺)

OR: [α]_(D) =⁺ 19.9 (C=0.5 in methanol)

UV (ethanol) λmax =315 (ε=2100), 286 (ε=1860), 2550 (ε=2550), and 268(ε=2430)

B. Deprotection

A 780 mg (1.21 mm) sample of the product from part A, above, wassuspended in a mixture of 20 ml THF and 20 ml of 1N HCl and stirred atroom temperature for 72 h. The reaction mixture was then diluted withethyl acetate, salted, and extracted (3×) with ethyl acetate. Thecombined ethyl acetate portions were washed with brine, dried overanhydrous MgSO₄, filtered, and concentrated in vacuo to afford 700 mg of3-β-phenoxyacetyl-4-β-phenylsulfonyl-4-β-dodecylazetidin-2-one as ayellow-white solid.

¹ H NMR (300 MHz, DMSO-d₆) δ 9.65 (S, 1H), 9.1 (d, 1H, J=8 Hz), 7.9-6.8(m, 10H), 5.38 (d, 1H, J=8 Hz), 4.6 (ABq, 2H), 1.6-1.0 (m, 22H), and0.85 (t, 3H, J=7 Hz)

IR (CHCl₃): 3020, 2956, 2929, 2857, 1790, 1702, 1518, and 1495 cm⁻¹

MS: m/e 529 (M⁺)

OR: [α]_(D) =⁺ 2.8 (C=0.5 in methanol)

UV (ethanol) λmax =268 (ε=2050)

C. Reduction

A 206 mg sample of the product from part B, above was dissolved in 10 mlof THF, cooled to 0° C., and treated with 200.2 mg (0.787 mm) of lithiumaluminum tri-t-butoxy hydride and stirred for 4 h. The reaction mixturewas then quenched with NaHCO₃ and extracted with ethyl acetate (4×). Thecombined ethyl acetate portions were dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to afford 156.2 mg of the titlecompound as a white solid.

Preparative thin layer chromatography (ethyl acetate as eluent) afforded102.9 mg of a white solid (74% yield).

¹ H NMR (300 MHz, DMSO-d₆) δ8.85 (d, 1H, J=8 Hz), 8.35 (s, 1H), 7.3-6.9(m, 5 H), 5.05 (dd, 1H, J=8, 5 Hz), 4.55 (S, 2H), 3.6 (m, 1H), 1.4-1.0(m, 22H), and 0.85 (t, 3H, J=7 Hz)

IR (CHCl₃): 3420, 2970, 2856, 1770, 1689, 1525, 1496, and 1238 cm⁻¹

UV (ethanol) λmax=268 (ε=1490)

OR: [α]_(D) =⁺ 42.9 (C=0.5 in methanol)

MS: m/e 389 (m⁺)

Example 4 3-β-Phenoxyacetylamino-4-β-methoxyethyl-azetidin-2-one A.Alkylation

A 1.00 g (2.11 mm) sample of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-1-t-butyldimethylsilylazetidin-2-onewas alkylated with methoxyethylbromide in THF using n-butyllithium asbase in a procedure analogous to that used in previous examples. Columnchromatography (silica gel, elution with CH₂ Cl₂ /ethyl acetate)afforded 641.4 mg of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-methoxyethyl-4-t-butyldimethylsilyl-azetidin-2-oneas a white solid (57% yield).

¹ H NMR (300 MHz, DMSO-d₆) δ 8.45 (d, 1H, J=8 Hz), 7.9-6.5 (m, 10H), 6.3(d, 1H, J=8 Hz), 4.38 (ABq, 2H), 3.4 (m, 2H), 3.2 (S, 3H), 2.2-1.4 (m,2H), 1.1 (S, 9H), 0.42 (S, 3H), and 0.38 (S, 3H)

IR (CHCl₃): 2931, 1772, 1690, 1601, 1527, 1494, and 1472 cm⁻¹

UV (ethanol) λmax=268 (ε=2040)

OR: [α]_(D) =⁺ 55 (C=0.5 in methanol)

MS: m/e 475 (M⁺ -C₄ H₉)

B. Deprotection

A 541.1 mg (1.017 mm) sample of the product from part A, above, wasdeprotected in a procedure analogous to that of the foregoing examplesto provide 431.4 mg of 4-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-methoxyethylazetidin-2-one as a white solid (101.4%).

¹ H NMR (300 MHz, DMSO-d₆) δ9.6 (S, 1H), 8.75 (d, 1H, J=8 Hz), 8.0-6.8(m, 10H), 5.5 (d, 1H, J=8 Hz), 4.6 (ABq, 2H), 3.4 (m, 2H), 3.2 (S, 3H),and 1.9 (m, 2H)

IR (CHCl₃): 1794, 1692, 1524, 1495, and 1309 cm⁻¹

UV (ethanol) λmax =290 (ε=15,900)

OR: [α]_(D) =⁺ 14.4 (C=0.5 in methanol)

MS m/e 276 (M⁺ -SO₂ C₆ H₅)

C. Reduction

A 114.8 mg sample of the product from part B, above, was reduced in aprocedure analogous to that of Example 4 above, using lithium aluminumtri-t-butoxy hydride as the reducing agent. Preparative thin layerchromatography (silica gel, ethyl acetate as eluent) afforded 50.9 mg(68% yield) of the title compound as a white solid.

¹ H NMR (300 MHz, DMSO-d₆) δ 8.55 (d, 1H, J=8 Hz), 6.08 (S, 1H), 5.42(dd, 1H, J=5, 8 Hz), 4.56 (S, 2H), 4.02 (m, 1H), 3.5 (m, 2H), 3.3 (S,3H), and 1.7 (m, 2H)

IR (CHCl₃): 3013, 1770, 1685, 1600, 1496, and 1237 cm⁻¹

UV (ethanol) λmax=269 (ε=1290)

OR: [α]_(D) =⁺ 41 (C=1.0 in methanol)

MS: m/e 278 (M⁺)

Example 5 3-β-Phenoxyacetylamino-4-β-ethyl-azetidin-2-one A. Alkylation

In a manner analogous to previous examples, a 2.00 g (4.22 mm) sample of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-1-t-butyldimethylsilyl-azetidin-2-onewas alkylated with ethyl bromide in THF using n-butyllithium as base toprovide 1.4353g of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-ethyl-1-t-butyldimethylsilyl-azetidin-2-oneas a white foam (68%)

¹ H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, 1H, J=8 Hz), 7.8-6.6 (m, 10H),6.15 (d, 1H, J=8 Hz), 4.4 (ABq, 2H), 2.2 (m, 1H), 1.2 (m, 1H), 1.1 (S,9H), 0.8 (t, 3H, J=8 Hz), 0.42 (S, 3H), and 0.38 (S, 3H).

IR (CHCl₃): 2934, 1765, 1702, 1600, 1519, and 1495 cm⁻¹

UV (ethanol) λmax=312 (ε=1010), 268 (ε=2140)

OR: [α]_(D) =⁺ 15.9 (C=0.5 in methanol)

MS: m/e 445 (M⁺ -C₄ H₉)

B. Deprotection

In a manner analogous to previous examples, a 1.23 g (2.4 mm) sample ofthe product from part A, above, was deprotected to afford 1.0410 g(112%) of3-β-phenoxyacetylamino-4-phenylsulfonyl-4-β-ethyl-azetidin-2-one as awhite solid, used in the next step without purification.

C. Reduction

In a procedure analogous to Example 5, above, a 134 mg sample of theproduct from part B, above, was reduced to afford (after preparativethin layer chromatography) 34.8 mg (46% yield) of the title compound.

¹ H NMR (300 MHz, CDCl₃) δ 7.4-7.0 (m, 5H), 6.9 (d, 1H, J=8 Hz), 6.4 (S,1H), 5.35 (dd, 1H, J=8, 5 Hz), 4.56 (S, 3H), 3.8 (m, 1H), 1.8-1.4 (m,2H), and 0.9 (t, 3H, J=7 Hz)

Example 6 3-β-Phenoxyacetyl-4-(α,β)(1-butene-4-yl)-azetidin-2-one

1-t-Butyldimethylsilyl-3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-butenyl-azetidinonewas prepared in a manner analogous to Example 1 above.

C. Reduction (1) NaBH₄

A 52.7 mg 0.1 mm sample of1-t-butyldimethylsilyl-3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-butenyl-azetidin-2-one(prepared in Example 1 above) was suspended in 2 ml of isopropanol and 1ml of H₂ O and treated with a molar excess of NaBH₄. Working up asbefore showed a mixture of cis (40.5%) and trans (59.5%) products (i.e.,α and β butenyl substituted azetidinone).

(2) NaCNBH₃

A 50.0 mg sample of1-t-butyldimethylsilyl-3β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-butenylazetidin-2-onewas dissolved in 2 ml of isopropanol and 1 ml of H₂ O and treated withNaCNBH₃. Workup and analysis indicated a cis/trans mixture with cispredominating (60/40 cis/trans).

(3) Zn(BH₄)₂

In a procedure analogous to 7(C)(1) and (2) above, the utilization ofZn(BH₄)₂ as reducing agent afforded a product comprised of mainly cisisomer (70/30 cis/trans).

(4) N(CH₃ CH₂ CH₂ CH₂)₄ BH₄

In a procedure analogous to 7(C) 1, 2, and 3, above N(CH₃ CH₂ CH₂ CH₂)₄BH₄ was utilized as the reducing agent. This reaction affordedpredominantly trans material, i.e.,3-β-phenoxyacetylamino-4-α-butenylazetidin-2-one (87/13 trans/cis).

Example 7 3-β-Phenoxyacetylamino-4-β-benzyl-azetidin-2-one A. Alkylation

In a procedure analogous to the foregoing examples, 1 g (2.11 mm) of3-β-phenoxyacetylamino-4-phenylsulfonyl-1-t-butyldimethylsilyl-azetidin-2-one was alkylated with benzyl bromideto afford 1.14 g of a yellow oily solid. Trituration of the crudeproduct with diethyl ether provided the pure product.

m.p.=121°-122° C.

NMR: 300 MHz (CDCl₃): δ 0.54 (S, 3H); 0.55 (S, 3H); 1.16 (S,9H); 2.83and 3.80 (ABq, 2H, J=15Hz); 4.19 and 4.29 (ABq, 2H, J=18Hz); 6.29 (d,1H, J=9Hz); 6.38 (d, 1H, J=9Hz); 6.53 (d, 2H, J=6Hz); 6.94-7.25 (m, 8H);7.60-7.79 (m, 3H); 8.14 (d, 2H, J=6Hz)

IR: (CHCl₃): 3017, 1770, 1696, 1517, 1496, 1310, 1150 cm⁻¹

MS: (FD) m/e=422 (m-142 (--SO₂ phenyl))

UV: (ethanol) λ=268 nm (ε=2440) λ=274 nm (s=2030)

OR: (methanol)=+82.68° at 365 nm

Elem. Anal. calc'd: C:63.80, H:6.43, N:4.96. obs'd: C:64.08, H:6.54,N:4.87.

B. Deprotection and C. Reduction

The product from Part A above, is deprotected and reduced in a manneranalogous to that taught in Example 4 to afford the title compound.

Example 8 3-β-Phenoxyacetylamino-4-β-allyl-azetidin-2-one A. Alkylation

In a procedure analogous to Example 4, above, a 5.0 g (10.55 mm) sampleof3-β-phenoxyacetylamino-4-α-phenylsulfonyl-1-t-butyldimethylsilyl-azetidin-2-onewas allylated with allyl bromide to form3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-allyl-1-t-butyldimethylsilyl-azetidin-2-oneas a dark yellow oil.

m.p=94°-96.5° C.

NMR: 300 MHz (CDCl₃): δ0.44 (S, 3H); 0.48 (S, 3H); 1.11 (S, 9H);2.06-2.14 (M, 1H); 3.10-3.22 (M, 1H); 4.27 and 4.45 (ABq, 2H, J=15Hz);4.86-4.95 (M, 1H); 5.24-5.31 (M, 1H); 5.64-5.88 (M, 1H); 6.26 (d, 1H;J=12Hz); 6.64 (d, 2H, J=9Hz); 6.94-7.26 (M, 3H); 7.10 (d, 1H, J=12Hz);7.58-7.78 (M, 3H); 8.60 (d, 2H, J=6Hz)

IR: (CHCl₃): 2970, 2940, 1770, 1698, 1519, 1495, 1310, 1155 cm⁻¹

MS (FD): m/e=515 (m+1)

UV (ethanol): λ=217 nm (ε=15,100), λ=267 nm (ε=1930), λ=274 nm (ε=1650),

OR (methanol): +90.04° at 365 nm

Elem. Anal. calc'd: C:60.67, H:6.66, N:5.44. obs'd: C:60.96, H:6.84,N:5.45.

B. Deprotection

1) A 4.76 g (11.9 mm) sample of the product from Part A, above, wasdissolved in a mixture comprised of 125 ml of THF and 125 ml 1N HCl andstirred at room temperature for 71/4 h. The reaction mixture was thendiluted with water and extracted with CH₂ Cl₂. The combined organicphase was washed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to provide a yellow semi-solid. Trituration of theproduct with diethyl ether afforded 1.66 g of a cream-colored solid.

2) A deprotection and reduction of the product of Procedure A, above,utilizing Red-A1® (sodium bis(2-methoxyethoxy) aluminum hydride)provided 3-β-phenoxyacetylamino-4-α,β-allyl-azetidin-2-one.

3) A deprotection and reduction of the product of Procedure A, above,using lithium aluminium tri-t-butoxy hydride provided3-β-phenoxyacetylamino-4-β-allyl-azetidin-2-one as the predominantproduct (ration of cis: trans=89:11).

m.p.=142°-144° C.

NMR 300 MHz (CDCl₃): δ 2.04-2.18 (M, 1H); 2.28-2.39 (M, 1H); 3.92-4.00(M, 1H); 4.54 (S, 2H); 5.04-5.17 (M, 2H); 5.33-5.41 (M, 1H); 5.64-5.79(M, 1H); 6.10 (br s, 1H); 6.89-7.38 (M, 6H)

IR (CHCl₃): 3023, 1773, 1688, 1600, 1524, 1496, 1237 cm⁻¹.

MS (FD): m/e=260 (M+)

UV (ethanol): λ=269 nm (ε=1430); λ=275 nm (ε=1180)

OR (DMSO): +263.9 at 365 nm

Elem. Anal. calc'd: C:64.60, H:6.20, N:10.76. obs'd: C:64.83, H:6.16,N:11.00.

4) A deprotection and reduction of the product of Procedure A, above,using NaBH<provided 3-β-phenoxyacetylamino-4-α,β-allyl-azetidin-2-one ina 1:1.7 ratio (cis:trans).

Example 9 3β-Phenoxyacetylamino-4-β-allyl-azetidin-2-one

A 78 mg (0.195 mm) sample of3-β-phenoxyacetylamino-4-α-allyl-4-β-phenylsulfonyl-azetidin-2-one wasdissolved in 3 ml of THF and cooled to 0° C. The substrate was thentreated with 110 mg (0.428 mm) of lithium aluminum tri-t-butoxy hydrideand stirred for about 45 min. The reaction mixture was then quenchedwith saturated NaHCO₃ solution and poured into an ethyl acetate/watermixture. The resulting mixture was made basic with 2N NaOH, and theorganic layer separated. The aqueous phase was extracted twice more withethyl acetate and the combined organics washed with brine, dried overanhydrous Na₂ SO₄, filtered, and concentrated in vacuo. Columnchromatography (9:1, ethyl acetate:hexane) provided 31 mg of the titlecompound.

NMR: 300 MHz (CDCl₃) δ =2.07-2.2 (M, 1H); 2.30-2.40 (M, 1H); 3.82-4.01(M, 1H); 6.31 (S, 1H); 6.90-7.41 (M, 6H)

IR (KBr): 3212.4, 1761, 1750, 1661, 1547, 1498, 1245, 1231 cm⁻¹

MS (FD): m/e=260 (M+)

UV ethanol): λ=268 nm (ε=1250), λ=275 nm (ε=1020)

OR (DMSO): +77.84° at 589 nm, +245.51° at 365 nm

Elem. Anal. calc'd: C:64.60, H:6.20, N:10.76. obs'd: C:64.83, H:6.17,N:10.52.

Example 10 3-β-Phenoxyacetylamino-4-β-methyl-azetidin-2-one A.Alkylation

In a procedure analogous to Example 4, above, a 1.0 g (2.11 mm) sampleof 3-β-phenoxyacetylamino-4-α-phenylsulfonyl-1-t-butyldimethylsilyl-azetidin-2-one was alkylated with methyl iodide to form3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-methyl-1-t-butyldimethylsilyl-azetidin-2-one.

m.p.=dec.>76° C.

NMR 300 MHz (CDCl₃): δ 0.40 (S, 3H); 0.42 (S, 3H) 1.05 (5.9H); 1.40(S.3M); 4.34 and 4.43 (Abq. 2H, J=15Hz); 5.64 (d, 1M, J=9 Hz); 6.69-7.24(M, 6H); 7.57-8.00 (M, 5H)

IR (KBr) 2930, 2860, 1768, 1749, 1691, 1308, 1254.5, 1153, 1069 cm⁻¹

MS (FAB) m/e=489 (M+), 347 (--SO₂)

UV (ethanol λ=218 nm (ε=16,400), λ=267 nm (ε=2020) λ=274 nm (ε=1660)

OR (DMSO): +41.98° at 589 nm, +171.76° at 476 nm,

Elem. Anal. Calc'd: C:58.99, H:6.60, N:5.73. Obs'd: C:59.19, H:6.73,N:5.68.

B. Deprotection

In a manner analogous to Example 11, below, the product from Part A,above, was deprotected.

NMR 300 MHz (DMSO-d⁶): δ 1.33 (S, 3H); 4.51 and 4.56 (Abq, 2H, J=9Hz);5.35 (d, 1H, J=9Hz); 6.83-7.23 (M, 5H); 7.62-7.86 (M, 5H); 9.04 (d, 1H,J=9Hz 9.41 (S, 1H)

IR (KBr) 3280, 3100, 1764, 1672, 1496, 1447, 1239, 1151, 1071 cm⁻¹

MS (FD) m/e=374 (M+), 232 (--SO₂ -phenyl)

UV (ethanol) λ=216 nm (ε=18,300), λ=268 nm (ε=2230), λ=275 cm (ε=1940)

OR (DMSO): +21.87° at 589 nm +117.30° at 375 nm,

Elem. Anal. calc'd: C:57.74, H:4.85, N:7.48. obs'd: C:57.46, H:4.59,N:7.31.

C. Reduction

In a manner analogous to Example 11, below, the product from Part B,above was reduced to provide the title compound.

m.p.=192°-194° C.

NMR 300 MHz (DMSO-d⁶): δ 0.99 (d, 3H, J=6Hz); 3.70-3.74 (M, 1H); 4.52(S, 2H); 4.96-5.01 (M, 1H); 688-7.27 (M, 5H); 8.17 (S,1H); 8.81 (d, 1H,J=3Hz)

IR (KBr) 3273, 2970, 1754, 1759, 1547, 1500, 1254 cm⁻¹

MS m/e=235 (M+)

UV λ=269 nm (ε=1360), λ=275 nm (ε=1130)

OR (DMSO): +80.00° at 589 nm +218.18° at 365 nm

Elem. Anal. calc'd: C:61.53, H:6.02, N:11.96. obs'd C:61.25, H:5.78,N:11.67.

Example 11 3-β-Phenoxyacetylamino-4-β-(4-pentene-1-yl)-azetidin-2-one A.Alkylation

A 1.0 g (2.11 mm) sample of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-1-t-butyldimethylsilylazetidin-2-one was dissolved in 10 ml of THF and cooled to -78° C. The substratewas then treated with 3.5 ml (1.49 M in hexane; 5.27 mm) ofn-butyllithium and stirred for about 30 min. The reaction mixture wasthen treated with 0.28 ml (2.33 mm) of 5-bromopent-1-ene and warmed to-40° C. After about 2.5 h, the reaction mixture was quenched with pH 4buffer, diluted with water and extracted (3 ×) with CH₂ Cl₂. Thecombined organics were washed with brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. Purification of the crude productafforded 773 mg (68%) of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-(4-pentene-1-yl)-1-t-butyldimethylsilyl-azetidin-2-one.

m.p.=129°-132° C.

NMR 300 MHz (CDCl₃): δ 0.38 (S, 3M); 0.42 (S, 3H); 1.07 (S,9H);0.87-1.25 (M, 2H); 1.39-1.50 (M, 1H); 1.67-1.79 (M, 2H); 2.10-2.23 (M,1H); 4.27 and 4.49 (ABq, 2H, J=15Hz); 4.84-4.92 (M, 2H); 5.50-5.63 (M,1H); 6.13 (d, 1H, J=12Hz); 6.59-7.18 (M, 6H); 7.57-8.03 (M, 5H)

IR (KBr): 1758, 1745, 1695, 1495, 1257, 1253, 1151, 2865, 2960 cm⁻¹

MS (FAB) m/e=543 (M+), 401 (--SO₂ phenyl)

UV (ethanol) λ=217 nm (ε=16,900), λ=267 nm (ε=2110), λ=274 nm (ε=1850)

OR (DMSO): +11.90° at 589 nm +61.90° at 365 nm

Elem. Anal. calc'd: C:61.96, H:7.06, ™N:5.16. obs'd: C:62.20, H:6.91,N:5.35.

B. Deprotection

A 680 mg (1.25 mm) sample of the product from Part A, above, wasdissolved in a mixture of 25 ml of 1N HCl and 15 ml of THF and stirredovernight. The reaction mixture was then diluted with water andextracted twice with CH₂ Cl₂. The combined organics were then washedwith brine, dried over anhydrous MgSO₄, filtered, and concentrated invacuo to provide a white solid. Trituration with diethyl ether andsubsequent drying afforded 396 mg of3-β-phenoxyacetylamino-4-α-phenylacetylamino-4-β-(4-pentene-1-yl)-azetidin.-2-one.

m.p.=146°-148° C.

NMR 300 MHz (CDCl₃): δ 1.35-1.97 (M, 4H); 4.49 (S, 2H); 4.89-4.95 (M,2H); 5.57 (d, 1H, J=9Hz); 5.56-5.70 (M, 1H); 6.77-7.32 (M, 6H);7.60-8.12 (M, 5H)

IR (KBr) 3300, 3200, 1776, 1668, 1535, 1496.5, 1306, 1228, 1148 cm⁻¹

MS m/e=429 (M+), 287 (--SO₂ phenyl)

UV (ethanol) λ=216 nm (ε=17,900), λ=268 nm (ε=2190), λ=275 nm (ε=1920)

OR (DMSO) +17.93° at 589 nm +71.71° at 365 nm

Elem. Anal. calc'd: C:61.67, H:5.65, H:6.54. obs'd: C:61.86, H.5.70,N:6.49.

C. Reduction

A 355 mg sample of the product from Part B, above, was dissolved in 7 mlof THF and cooled to about 0° C. The substrate was then treated withlithium aluminum tri-t-butoxy hydride and stirred for about 45 min. Thereaction mixture was then quenched with saturated NaHCO₃ solution,diluted with 2N NaOH and extracted with ethyl acetate (2×). The combinedorganics were then washed with brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to provide the crude product. Columnchromatography (silica gel, 80% ethyl acetate, 20% hexane) provided 184mg (77% yield) of the title compound as a white solid. The crude productappears to have been produced in a ratio of cis:trans of 93:7.

m.p.=114°-117° C.

300 MHz (CDCl₃): δ 1.32-1.53 (M, 4H); 1.98-2.04 (M, 2H); 3.82-3.87 (M,1H); 4.53 (S, 2H); 4.92-5.00 (M, 2H); 5.31-5.35 (M, 1H); 5.66-5.79 (M,1H); 6.16 (S, 1H); 6.90-7.34 (M, 5H); 7.16 (d, 1H, J=9Hz)

IR (KBr): 3230, 2940, 1763, 1753, 1657, 1545, 1498, 1240 cm⁻¹

MS (FD) m/e 288 (M+)

UV λ=269 (ε=1370) λ=275 (ε=1130)

OR +80.55° at 589 nm, +264.24° at 365 nm

Elem. Anal. calc'd: C:66.65, H:6.99, N:9.72. obs'd C:66.68, H.6.78,N:9.63.

Example 12 3-β-Phenoxyacetylamino-4-α-methylazetidin-2-one

A 600 mg sample of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-methyl-azetidin-2-one (seeExample 11) (1.60 mm) was dissolved in 40 ml of THF, cooled to 0° C. andtreated with 825 mg (3.20 mm) of tetrabutyl ammonium borohydride andstirred for about 50 min. The reaction mixture was then quenched withsaturated NaHCO₃ solution, diluted with water, and extracted (2×) withCH₂ Cl₂. The combined organic portions were washed with brine, driedover anhydrous Na₂ SO₄, filtered, and concentrated in vacuo. Columnchromatography (silica gel, 10% hexane/90% ethyl acetate to 100% ethylacetate) provided 288 mg (77%) of the title compound as a white solid.Analysis showed the crude product to exist in a 8:92 cis:trans ratio.

m.p.=164°-166°

NMR: MHz (DMSO-d⁶): δ 1.20 (d, 3H J=6Hz); 3.53-3.56 (M, 1H); 4.33-4.37(M, 1H); 4.46 (S, 2H); 6.90-7.28 (M, 5H); 8.11 (S, 1H); 8.75 (d, 1H,J=9Hz)

IR (KBr) 3280, 2915, 1759.4, 1658.3, 1546.7, 1499, 1254 cm⁻¹

MS (FAB) m/e=235 (M+1)

UV (ethanol) λ=275 nm (ε=1060), λ=269 nm (ε=1270)

OR (DMSO) -57.49° at 589 nm, -174.22° at 365 nm

Elem. Anal. calc'd: C:61.53, H:6.02, N:11.96. obs'd: C:61.35, H:5.97,N:11.80.

Example 133-β-Phenoxyacetylamino-4-β-(3-chloro-2-hydroxy-prop-1-yl)azetidin-2-oneA. Alkylation

In a procedure analogous to that of Example 11,3β-phenoxyacetylamino-4-α-phenylsulfonyl-1-t-butyldimethylsilyl-azetidin-2-onewas alkylated with 1-chloro-2,3-epoxypropane to provide3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-(3-chloro-2-hydroxy-prop-1yl)-1-t-butyldimethylsilyl-azetidin-2-onein 20% yield.

m.p. (dec.) =>165°

NMR 300 MHz (CDCl₃): 0.36 (S, 3H); 0.39 (S, 3H); 0.89-0.99 (M, 1H) 1.07(S, 9H); 2.24-2.29 (M, 1H); 2.52-2.59 (M, 1H); 2.84 (S, 1H); 3.07-3.12(M, 1H); 4.80-4.90 (M, 1H); 4.20 and 4.51 (ABq, 2H, J=15Hz); 6.31 (d,1H, J=12 Hz); 6.39-7.05 (M, 5H); 7.62-8.01 (M, 5H); 8.44 (d, 1H, J=9Hz)

IR (KBr): 3281, 1768.5, 1661, 1309, 1210.5, 1155 cm⁻¹

MS (FAB) m/e=567 (M+), 425 (--SO₂ phenyl)

UV (ethanol) λ=218 nm (ε=14,900), λ=268 nm (ε=1920), λ=274 nm (ε=1630)

OR (DMSO) +42.59° at 589 nm, +198.15° at 365 nm

Elem. Anal. calc'd: C:55.06, H:6.22, N:4.95. obs'd: C:54.86, H:6.18,N:4.89.

B. Deprotection

In a procedure analogous to that of Example 12,3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-(3-chloro-2-hydroxy-prop-1-yl)-1-t-butyldimethylsilylazetidin-2-onewas converted to3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-(3-chloro-2-hydroxy-prop-1-yl)-azetidin-2-onein 75% yield.

m.p. (dec.) >95° C.

300 MHz (CDCl₃) δ 1.43-1.52 (M, 1H); 2.26 (d, 1H, J=15Hz); 2.92-2.99 (M,1H); 3.22-3.27 (M, 1H); 3.65 (S, 1H); 4.03-4.05 (M, 1H); 4.41 and 4.53(ABq, 2M, J=15 Hz): 5.87 (d, 1H, J=9Hz); 6.69-7.20 (M, 5H); 7.39 (S,1H); 7.62-8.03 (M, 5H); 8.41 (d, 1H, J=9Hz)

IR (KBr) 3327, 1791, 1675, 1523, 1495, 1306, 1151 cm⁻¹

MS (FAB) m/e=452 (M-1), 311 (--SO₂ phenyl)

UV (ethanol) λ=216 nm (ε 17,400),

λ=268 nm (ε=2500),

λ=275 nm (ε=2200)

OR (DMSO) +15.59° at 589 nm,

+68.23° at 365 nm

Elem. Anal. calc'd C:53.04, H:4.67, N:6.19. obs'd: C:53.09, H.4.68,N:6.31.

C. Reduction

In a procedure analogous to that of Example 11,3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-(3-chloro-2-hydroxy-prop-1-yl)-azetidin-2-onewas converted to3-β-phenoxyacetylamino-4-β-(3-chloro-2-hydroxy-prop-1-yl)-azetidin-2-onein 45% yield.

m.p. (dec.) 135°-140° C.

NMR 300 MHz (DMSO-d₆): δ 1.49-1.68 (M, 2H);

3.36-3.47 (M, 2H); 3.52-3.59 (M, 1H); 3.73-3.79 (m, 1H); 4.50 (S, 2H);5.03-5.07 (M, 1H); 5.19 (d, 1H, J=6Hz); 6.88-7.27 (M, 5H); 8.15 (S, 1H);8.87 (d, 1H, J=9Hz)

IR (KBr) 3457, 3355, 1756, 1735, 1163, 1536, 1497, 1214, 1062 cm⁻¹

MS (FAB) m/e=313 (M+)

UV (ethanol) λ=269 (ε=1500),

λ=275 (ε=1270)

OR (DMSO): +27.73° at 589 nm,

+105.36° at 365 nm

Elem. Anal. calc'd: C:53.77, H:5.48, N:8.96. obs'd: C:53.51, H:5.41,H:8.73.

Example 14 3β-Phenoxyacetylamino-4-β(2-fluoroeth-1-yl)-azetidin-2-one A.Alkylation

In a manner analogous to the foregoing examples,1-t-butyldimethylsilyl-3-β-phenoxyacetylamino-4-α-phenylsulfonyl-azetidin-2-onewas alkylated with 1-bromo-2-fluoroethane.

m.p. (dec.) 158°-159° C.

NMR 300 MHz (CDCl₃): δ 0.36 (S, 3H); 0.44 (S, 3H); 1.09 (S,9H);1.55-1.64 (M, 1 Hz); 2.22-2.43 (M, 1H); 4.28 and 4.47 (ABq, 2H, J=15Hz)4.33-4.70 (M, 2H); 6.30 (d, 1H, J=12 Hz); 6.58-7.14 (M, 5H); 7.58-8.02(M, 5H)

IR (KBr); 3408, 1761, 1700, 1533, 1497, 1310, 1266, 1233, 1150 cm⁻¹

MS (FAB) m/e=521, 379 (--SO₂ phenyl)

UV (ethanol) λ=217 nm (ε=17,500), λ=268 nm (ε=2270), λ=274 nm (ε=1870)

OR (DMSO) +29.23° at 589 nm, +119.00° at 365 nm

B. Deprotection

m.p. (dec.) 152°-154° C.

NMR 300 MHz (CDCl₃): δ 1.97-2.12 (M, 1H); 2.24-2.44 (M, 1H); 4.50 (S,2H); 4.55-4.69 (M, 1H); 4.78-4.87 (M, 1H); 5.72 (d, 1H, J=12Hz)6.78-7.25 (M, 5H); 6.87 (S, 1H); 7.43-7.78 (M, 5H); 8.05 (d, 1M J=9H)

IR (KBr) 3300, 1771, 1674, 1532, 1496, 1332, 310, 1226, 1151 cm⁻¹

MS (FAB) m/e=407 (M+), 265 (--SO₂ phenyl)

UV (ethanol) λ=216 nm (ε=17,800), λ=268 nm (ε=2300), λ=275 nm (ε=2030)

OR (DMSO): +12.02° at 589 nm, +66.13° at 365 nm

Elem. Anal. calc'd: C:56.15, H:4.71, N:6.89. obs'd: C:56.39, H:4.83,N:7.02.

C. Reduction ratio of cis/trans 91:9

m.p (dec.) 180°-182° C.

NMR 300 MHz (DMSO-d₆): δ 1.65-1.80 (M, 2H); 3.69-3.73 (M, 1H); 4.29-4.33(M, 1H); 4.44-4.48 (M, 1H); 4.52 (S, 2H); 5.06-5.11 (M, 1H); 6.88-7.27(M, 5H); 8.35 (S, 1H); 8.86 (d, 1H, J=9Hz)

IR (KBr) 3268, 3262, 3082, 1771, 1731, 1669, 1557, 1223, 1027 cm-¹

MS (FD) m/e=266 (M+)

UV (ethanol) λ=269 nm (ε=1310), λ=275 nm (ε=1070)

OR (DMSO): +75.85° at 589 nm, +231.54° at 365 nm

Elem. Anal. calc'd: C:58.64, H:5.68, N:10.51. obs'd: C:58:82, H:5.78,N:10.60.

Example 15 3-β-Phenoxyacetylamino-4-β-(2-hydroxyeth-1-yl)-azetidin-2-oneA. Alkylation

In a manner analogous to the foregoing examples,1-t-butyldimethylsilyl-3-β-phenoxyacetylamino-4-α-phenylsulfonylazetidin-2-one was alkylated with ethylene oxide to provide1-t-butyldimethylsilyl-3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-(2-hydroxyeth-1-yl)-azetidin-2-one.

m.p.=143-146° C.

MR 300 MHz (CDCl₃): δ 0.36 (S, 3H); 0.42 (S, 3H); 1.08 (S, 9H);1.24-1.40 (M, 1H); 2.03-2.25 (M, 2H); 3.61-3.82 (M, 2H); 4.22 and 4.39(ABq, 2H, J=15 Hz); 6.32 (d, 1H, J=12Hz); 6.52-7.10 (M, 5H); 7.56-8 00(M, 5H); 8.64 (d, 1H, J=12 Hz)

IR (KBr) 3518, 2940, 1754, 1692, 1303, 1264, 212, 1150 cm⁻¹

MS m/e=519 (M+)

UV (ethanol) λ=217 nm (ε=16,400), λ=268 nm (ε=2030), λ=274 nm (ε=1700)

OR (DMSO): +56.93° at 589 nm, +235.29° at 365 nm

Elem. Anal. calc'd C:57.89, H:6.61, N:5.40. obs'd: C:57.81, H:6.50,N:5.65.

B. Deprotection

m.p.(dec.)>90° C.

300 MHz (CDCl₃): δ 1.70-1.80 (M, 1H); 2.16 (d, 1H, J=15 Hz); 2.76 (S,1H); 3.69-3.90 (M, 2H); 4.42 and 4.49 (Abq, 2H, J=15 Hz); 5.91 (d, 1H,J=12Hz); 6.72-7.19 (M, 5H); 7.36 (S, 1H) 7.59-8.01 (M, 5H); 8.56 (d, 1H,J=12 Hz)

IR (KBr) 3296, 3202, 1787, 1672, 1527, 1495, 1305, 1239, 1151, 1071 cm⁻¹

MS (FAB) m/e=405 (M+), 263 (--SO₂ phenyl)

UV (ethanol) λ=218 nm (ε=16,500), λ=268 nm (ε=2120), λ=274 nm (ε=1780)

OR (DMSO) +19.69° at 589 nm, +74.80° at 365 nm

Elem. Anal. calc'd: C:56.42, H:4.98, N:6.92. obs'd: C:56.06, H:5.14,H:6.73.

C. Reduction

m.p. (dec.)>185° C.

NMR 300 MHz (DMSO-d₆): δ 1.45-1.53 (M, 2H); 3.31-3.35 (M, 2H); 3.67-3.73(M, 1H); 4.46-4.50 (S, 3H); 5.01-5.06 (M, 1H); 6.88-7.27 (M, 5H); 8.25(S, 1H); 8.84 (d, 1H, J=9Hz)

IR (KBr): 3269, 1754, 1715, 1673, 1558, 1496, 1222 cm⁻¹

MS (FAB) m/e=265 (M+1)

UV (ethanol) λ=268 nm (ε=1420) λ=275 nm (ε=1170)

OR (DMSO): +56.20° at 589 nm, +203.49° at 365 nm

Elem. Anal. calc'd: C:59.08, H:6.10, N:10.60. obs'd: C:58.61, H:6.02,N:10.15.

Example 16 7β-Phenoxyacetylamino-4-methylazetidin-2-one A. Alkylation

A sample of7-β-phenoxyacetylamino-4-α-phenylsulfonyl-1-t-butyldimethylsilyl-azetidin-2-oneis alkylated using n-butyllithium and methyl iodide.

B. Electrolytic Reduction and Deprotection

The cathode compartment was fitted with a mercury ring cathode and amagnetic stirring bar. The cathode compartment was then charged with 55ml of a 0.1 molar solution of tetrabutylammonium hydrogen sulfatedissolved in dimethylformamide. The solution was kept at a constanttemperature of about 25° C. by means of a circulating refrigerated bath.Dissolved in the cathode was 283.8 mg of3-β-phenoxyacetylamino-4-α-phenylsulfonyl-4-β-methyl-1-t-butyldimethylsilylazetidin-2-one.

The anode compartment was fitted with a platinum wire anode, an anolytepresoaked Nafion® 425 cation exchange membrane, and charged with a 0.25molar solution of pH 2.7 sodium phosphate buffer. The anode compartmentwas then positioned within the cathode compartment. The anodecompartment was charged with sufficient anolyte such that the level ofthe anolyte was approximately the same as the level of the catholyte. Atthis point, the catholyte was deoxygenated using a stream of inert gasand bubbler. The electrodes were then attached to the appropriateterminals of a potentiostat and a controlled potential of -2.2 V(vs.S.C.E.) was applied. The reaction proceeded at this potential untilcomplete as determined by TLC.

The catholyte solution was rotoevaporated to near dryness and applied toa liquid chromatography column (5 cm dia. filled to 15 cm with Kiesegel60; flow rate=40 ml/min.; eluent=acetone; pressure=7 psi). Theappropriate chromatography fractions were reduced in volume under vacuumto produce 114.2 mg of the desired product. The product was produced at51 percent current efficiency and recovered at 84 percent (cis andtrans) of theoretical yield.

NMR of cis product (270 MHz; DMSOd₆): d, 1.03; m, 377; s, 4.57; dd,5.04; m, 6.97; m, 7.32; m, 8.50.

We claim:
 1. A process for preparing compounds of Formula (I) ##STR9##wherein R is a protected amino group; hydroxy(C₁ -C₄)alkyl, protectedhydroxy(C₁ -C₄)-alkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkyl or hydrogen; R² isC₁ -C₁₂ alkyl, C₁ -C₁₂ substituted alkyl, C₂ -C₆ alkenyl, C₂ -C₆substituted alkenyl, C₂ -C₆ alkynyl or C₂ -C₆ substituted alkynyl; andR³ is an amide-protecting group, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, orhydrogen; which comprises(a) reaction of a compound of Formula (II):##STR10## wherein R¹ is triphenylphosphonium, --SO₂ R', CN, or ##STR11##wherein R' is C₁ -C₆ alkyl, phenyl, substituted phenyl, phenyl C₁ -C₆alkyl, or C₁ -C₆ substituted alkyl; and R and R³ have the same meaningsas defined for Formula (I); with strong base in the presence of acompound of the formula R² --L, wherein L is a leaving group; and R² hasthe same meanings as defined for Formula (I); followed by (b) reductionunder electrolytic reduction conditions.
 2. The process of claim 1wherein R¹ is --SO₂ R'.
 3. The process of claim 2 wherein R¹ is --SO₂ R'and R' is phenyl.
 4. A process for preparing compounds of Formula (I)##STR12## wherein R is a protected amino group, hydroxy(C₁ -C₄)alkyl,protected hydroxy (C₁ -C₄)alkyl, hydrogen, C₂ -C₄ alkenyl, or C₁ -C₄alkyl; R¹ is triphenylphosphonium, --SO₂ R', CN, or ##STR13## wherein R'is C₁ -C₆ alkyl, phenyl, substituted phenyl, phenyl C₁ -C₆ alkyl, or C₁-C₆ substituted alkyl; R² is C₁ -C₁₂ alkyl, C₁ -C₁₂ substituted alkyl,C₂ -C₆ alkenyl, C₂ -C₆ substituted alkenyl, C₂ -C₆ alkynyl, or C₂ -C₆substituted alkynyl; and R³ is an amide-protecting group, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, or hydrogen which comprises subjecting acompound of Formula (III) ##STR14## (a) to electrolytic reduction.